Search Results (596)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by early metastasis, dense desmoplastic stroma and a profoundly immunosuppressive, lymphocyte-depleted tumor microenvironment that severely limits the efficacy of current systemic and immunotherapeutic approaches. Oncolytic viruses (OVs), which selectively replicate in and lyse malignant cells while activating antitumor immunity, have emerged as attractive candidates to convert this “cold” tumor into a more inflamed and therapeutically responsive disease. In this review, we summarize clinical evidence on the main OV platforms evaluated in PDAC, including adenovirus, herpes simplex virus, vaccinia virus, parvovirus and reovirus, with a focus on clinical trials. Across these classes of viruses, intratumoral administration has consistently proven feasible and generally well tolerated, with frequent evidence of viral replication, microenvironmental remodeling and immune activation, but only modest and often transient antitumor responses in small, early-phase cohorts. We then discuss key biological and translational challenges that currently limit OV impact in PDAC, such as systemic delivery in the context of pre-existing antiviral immunity and rapid clearance, penetration through the fibrotic stroma, and rational selection of encoded transgenes to reshape myeloid cell-driven, pro-tumoral inflammation and enhance T-cell recruitment. Finally, we outline future directions for the field, including carrier-cell–based systemic delivery, stroma-targeting or cytokine-armed constructs, and combinatorial strategies with chemotherapy and immune checkpoint blockade, arguing that design refinement, innovative combinations and mechanism-driven trial designs will be essential to unlock the full therapeutic potential of oncolytic virotherapy in PDAC. Full article

Background/Objectives: Glioblastoma remains the most lethal primary brain tumor in adults, and progress in oncolytic virotherapy is limited by the lack of immunocompetent models permissive to human-tropic viruses. Methods: Here, murine CT-2A and GL261 glioma and B16 melanoma cell lines were engineered to express human Coxsackievirus and Adenovirus Receptor (CXADR) fused to tagBFP, generating “humanized” tumors that preserve parental growth characteristics while acquiring high susceptibility to group B Coxsackieviruses (CVBs) and adenovirus serotype 5. Results: CXADR expression in CT-2A, GL261, and B16 cells markedly enhanced binding, internalization, and replication of CVBs in vitro, with the strongest effect observed for LEV14 (attenuated CVB5), which reached up to 10⁵-fold higher viral titers in humanized cells compared with parental cells. Unchanged sensitivity to vesicular stomatitis virus indicated receptor-specific effects. Humanized CT-2A-CXADR-BFP and GL261-CXADR-BFP cells initiated aggressive subcutaneous and intracranial tumors in syngeneic C57BL/6 mice without signs of immune rejection, and histology and MRI confirmed invasive high-grade glioma phenotypes. In intracranial CT-2A-CXADR-BFP tumors, repeated intratumoral LEV14 administration induced extensive tumor necrosis and prolonged survival despite the rapid development of neutralizing antibodies. Systemic intravenous LEV14 dosing produced strong oncolytic activity against subcutaneous CT-2A-CXADR-BFP tumors, as demonstrated by pronounced tumor growth inhibition, long-lasting regression in a subset of animals with gliomas, and improved overall survival. Conclusions: Collectively, these data establish CXADR-humanized models as versatile, immunocompetent platforms for evaluation of CXADR-dependent oncolytic enteroviruses. Full article

Oncolytic viruses represent a paradigm-shifting approach to cancer immunotherapy, functioning as in situ vaccines that convert immunologically “cold” tumors into “hot” tumors through induction of immunogenic cell death (ICD). Despite the clinical success of checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), many patients exhibit primary or acquired resistance due to insufficient tumor immunogenicity and exclusion of tumor-infiltrating lymphocytes. Oncolytic viruses address this limitation by selectively replicating in tumor cells, inducing robust ICD characterized by four cardinal hallmarks: calreticulin exposure, ATP secretion, HMGB1 release, and type I interferon production. This review systematically examines the molecular mechanisms underlying virus-induced ICD, compares DNA virus platforms (Vaccinia, HSV-1, Adenovirus) with RNA virus platforms (Coxsackieviruses A21, A11, and B3), and analyzes clinical trial data demonstrating synergistic efficacy when combined with checkpoint inhibitors. Notably, RNA viruses generate higher type I interferon responses compared to DNA viruses, correlating with superior clinical outcomes. Coxsackievirus A21 combined with pembrolizumab achieved a 47% objective response rate in melanoma in the CAPRA trial, representing notable efficacy exceeding either monotherapy. Coxsackievirus A11 demonstrates exceptional selectivity for thoracic cancers through ICAM-1-dependent receptor tropism and potent immunogenic cell death induction. Japanese researchers have pioneered microRNA-targeted Coxsackievirus B3, achieving cardiac safety attenuation while preserving complete oncolytic potency and ICD-inducing capacity. This comprehensive analysis synthesizes molecular mechanisms, platform comparisons, clinical efficacy data, and translational challenges to guide future development of oncolytic virotherapy as a cornerstone of cancer immunotherapy. Full article

Background/Objectives: Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and the high prevalence of malignant ascites, a hallmark of advanced disease that is difficult to control and contributes to immune suppression and treatment failure. Despite advances in standard care, durable responses are rare. This study investigates a novel immunotherapeutic strategy designed to overcome the suppressed peritoneal microenvironment using an oncolytic vaccinia virus engineered to express a decoy-resistant IL-18 mutein. Methods: We generated a vaccinia virus (vvDD-nsmDR-18) expressing a non-secreted, mature, decoy-resistant IL-18. Viral expression was validated via RT-qPCR and fluorescence microscopy, while cytotoxicity was confirmed using CCK-8 assays. The antitumor efficacy of vvDD-nsmDR-18 was evaluated in the aggressive murine ID8a ovarian cancer model. The underlying mechanisms of action were investigated using flow cytometry and transcriptional profiling. Results: Treatment with vvDD-nsmDR-18 significantly prolonged survival and was associated with reduced abdominal distension consistent with decreased ascites burden. Immune analyses indicated enhanced T cell activation across multiple anatomical compartments, including tumors, peritoneal cavity, and spleens, the latter recently suggested to serve as a reservoir for tumor-reactive T cells. This systemic activation was characterized by increased IFN-γ and perforin expression. In addition, vvDD-nsmDR-18 treatment was associated with expansion of CD39⁺CD103⁺CD8⁺ tumor-reactive T cells and a shift toward a lower PD-1 expression phenotype within this population. Conclusions: These findings demonstrate that nsmDR-18-expressing oncolytic viruses can remodel the immunosuppressive landscape of advanced ovarian cancer, suggesting this approach is a promising candidate for further clinical development. Full article

The α-gal epitope is synthesized in non-primate mammals and New-World monkeys by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT), encoded by the GGTA1 gene. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent extinction 20–30 million years ago. Their mutated offspring, with the inactivated GGTA1 gene, survived and produced the natural anti-Gal antibody, specifically binding α-gal epitopes. Anti-Gal protected the surviving offspring from lethal viruses presenting α-gal epitopes, which killed α-gal-synthesizing parental primates. Anti-Gal constitutes ~1% of human immunoglobulins and is also produced in Old-World monkeys and apes. α-Gal epitopes can serve as therapeutic agents in several clinical disciplines: 1. Cancer immunotherapy: Engineering cancer cells to express α-gal epitopes results in anti-Gal binding to these cells and localized activation of the complement system that kills these cancer cells and recruits the antigen-presenting cells (APCs) dendritic cells and macrophages. Anti-Gal bound to cancer cells targets them for robust uptake by APCs, which process internalized tumor antigens (TAs) and transport them to lymph nodes for activation of cytotoxic T-cells. These T-cells kill TA-presenting metastatic tumor cells. Clinical trials demonstrated that such engineering is achieved by intra-tumoral injection of α-gal glycolipids, the use of recombinant α1,3GT, or the use of oncolytic viruses containing the GGTA1 gene. 2. Viral vaccines: Inactivated whole-virus vaccines presenting α-gal epitopes bind anti-Gal, which targets them for extensive uptake by APCs, thereby increasing their immunogenicity by ~100-fold. 3. Injured-tissue regeneration: Anti-Gal binding to α-gal-presenting nanoparticles administered to wounds, into the post-myocardial infarction (MI) injured myocardium and into injured spinal cord, activates the complement system that recruits pro-regenerative macrophages, which orchestrate regeneration by recruiting stem cells and the secretion of pro-regenerative cytokines. All these findings suggest that α-gal/anti-Gal antibody interaction can serve as a novel therapeutic approach, applicable to various clinical settings. Full article

Avian reovirus (ARV) is a major poultry pathogen recently recognized for its potential as an oncolytic virus that selectively infects and kills cancer cells without harming healthy human cells. However, the receptors mediating ARV entry into cancer cells remain unclear. Using mouse melanoma B16-F10 cells as a model, this study identified ARV-binding receptor candidates through viral overlay protein binding assay (VOPBA), SDS-PAGE, and LC-MS/MS analysis. Plaque-forming assays (PFAs) evaluated viral replication efficiency, while co-immunoprecipitation (Co-IP) and proximity ligation assay (PLA) confirmed direct interactions between viral σC and host receptor proteins. Functional assays using shRNA knockdown and antibody blocking demonstrated that inhibition of Plg-RKT expression markedly reduced ARV infection. Western blot analysis revealed that ARV binding to Plg-RKT activates Src and p38 MAPK signaling pathways, which promote caveolin-1 phosphorylation and caveolae-mediated endocytosis. These findings identify Plg-RKT as a crucial receptor mediating ARV σC binding and entry into B16-F10 melanoma cells. Furthermore, activation of Src-p38 MAPK signaling was shown to be essential for viral internalization. This study elucidates the molecular mechanism underlying ARV entry into melanoma cells and provides valuable insight for improving the selectivity and therapeutic potential of ARV as an oncolytic virus. Full article

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically ‘cold’ tumors into ‘hot’ ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects of the double recombinant vaccinia virus VV-GMCSF-Lact, which carries the human GM-CSF gene, with those of recombinant human GM-CSF (rhGM-CSF) in an immunocompetent murine GL261 glioma model. Methods: The study was conducted using a subcutaneous GL261 glioma model in immunocompetent C57BL/6 mice, comparing intratumoral VV-GMCSF-Lact and rhGM-CSF treatments with evaluation of immune cell populations by flow cytometry, tumor morphology by H&E staining, and tumor transcriptome profiles by RNA sequencing. Results: Flow cytometry showed that VV-GMCSF-Lact reduced the number of immunosuppressive cells in the TME of subcutaneously transplanted gliomas, targeting different components of the TME depending on animal sex. The immunotherapeutic effects of rhGM-CSF were less pronounced and primarily affected peripheral immune cells. Histological analysis revealed a decrease in mitotic figures in tumors from female mice after viral therapy. Transcriptome profiling of GL261 tumors demonstrated divergent gene expression patterns and cellular compositions between treatment groups. VV-GMCSF-Lact treatment was associated with a decreased proportion of malignant GL261 cells and CD8⁺ T lymphocytes, while rhGM-CSF treatment increased proportions of MDSCs, macrophages, NK cells, and tumor-associated neutrophils. Conclusions: Taken together, our data demonstrate that VV-GMCSF-Lact induces antitumor immune responses in murine GL261 glioma in vivo and modulates the tumor microenvironment more effectively than rhGM-CSF alone, supporting its potential for developing new strategies for glioma treatment. Full article

Vesicular stomatitis virus (VSV) is a promising oncolytic virus whose replication efficiency and tumor selectivity are strongly influenced by host cell metabolism. Cancer cells, including glioblastoma, exhibit profound rewiring of central carbon metabolism to sustain proliferation, redox balance, and biosynthetic demand, yet how these metabolic states regulate VSV replication remains incompletely defined. Here, we investigated the dependency of VSV replication on glycolysis, the pentose phosphate pathway (PPP), and glutamine metabolism in A172 human glioblastoma cells. Pharmacologic inhibition of glycolysis using 2-DG strongly suppressed VSV replication in a dose-dependent manner, highlighting a robust requirement for glycolytic flux and downstream intermediates. While inhibiting the PPP with 6-AN, a nicotinamide adenine dinucleotide (NAD) analog, markedly impaired viral replication, D-ribose was unable to rescue the inhibition, indicating that nucleotide precursor limitation alone was insufficient to explain this effect. Interestingly, depletion of glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the PPP, resulted in significant enhancement of VSV replication. Restoration of viral replication by NAD⁺ precursors in the presence of 6-AN or suppression of replication by the NAMPT inhibitor FK866 suggested NAD⁺ availability as a critical determinant of VSV replication. Additionally, blockade of glutaminase activity with BPTES reduced viral replication, underscoring the importance of anaplerotic pathways in glioblastoma cells. Collectively, these findings demonstrate that VSV replication is tightly coupled to metabolic programs, particularly those governing energy production and NAD(P)H balance. This work provides a metabolic framework for optimizing oncolytic VSV therapies and suggests that metabolic interventions in cancer treatment may influence oncolytic virus efficacy. Full article

Neoantigen vaccines have revitalized cancer vaccination by targeting tumor-specific mutant epitopes largely absent from central tolerance. Yet, clinical benefits remain inconsistent, in part because conventional vaccine platforms often do not reliably deliver antigens within an inflammatory tumor context, struggle to overcome immunosuppressive tumor microenvironments, and may not rapidly adapt to tumor heterogeneity and evolution. Oncolytic viruses (OVs) provide a mechanistically distinct route to “vaccinate in situ” by coupling tumor-selective infection and immunogenic cancer cell death with local innate immune activation, antigen release, and remodeling of the tumor microenvironment. In parallel, advances in sequencing, neoantigen prediction (e.g., updated NetMHCpan and MHCflurry tools as of 2025), and antigen presentation validation have enabled rational selection of patient-specific targets. At the same time, modern OV engineering supports insertion of neoantigen payloads and immune-modulatory transgenes. Here, we summarized principles that underpin neoantigen-encoded OVs as personalized cancer vaccines, emphasizing how OV adjuvanticity and antigenicity interact to drive priming, epitope spreading, and durable systemic immunity. We discussed major OV platforms with respect to payload capacity, expression control, manufacturability, and clinical track records, including lessons learned from approved or late-stage OVs such as talimogene laherparepvec (T-VEC) and teserpaturev/G47Δ. We also discussed design choices for encoding neoantigens (polyepitope strings, minigenes, long peptides; class I/II balancing), prioritizing translational biomarkers and immune-monitoring strategies, and outlining regulatory and GMP considerations for “platform-plus-variable insert” products. Finally, we propose a pragmatic clinical workflow for rapid personalization to maximize therapeutic index. Tightly integrating neoantigen science with immunovirotherapy, including recent 2025 preclinical advances like oncolytic adenovirus neoantigen delivery sensitizing low-TMB tumors to PD-1 blockade, could enable next-generation personalized cancer vaccines capable of converting “cold” tumors into responsive, systemically controlled disease. Full article

Cancer immunotherapy has transformed modern oncology, yet durable responses remain limited for many patients due to immune exclusion, adaptive resistance, and tumor heterogeneity. Oncolytic viruses (OVs) have emerged as a novel class of immunotherapeutics that unify direct tumor cytolysis with stimulation of antitumor immunity. By inducing immunogenic cell death (ICD) and releasing tumor-associated antigens (TAAs), OVs remodel the tumor microenvironment (TME) into an inflamed and immune-permissive niche capable of enabling systemic immune activation. Rapid advances in viral engineering have strengthened the translational potential of OVs through tumor-selective gene deletions, tumor-specific promoters, microRNA-based detargeting, and receptor-retargeting strategies that collectively enhance safety, specificity, and intratumoral propagation. Next-generation OVs are increasingly “armed” with immunostimulatory payloads—including cytokines, chemokines, checkpoint inhibitors, bispecific T-cell engagers, and suicide gene systems—allowing localized immune modulation with reduced systemic toxicity. These innovations have propelled significant clinical progress, exemplified by the approvals of talimogene laherparepvec (T-VEC), G47Δ, and H101, and have driven a surge of combination trials integrating OVs with immune checkpoint blockade, adoptive cell therapies, radiotherapy, and targeted therapies to overcome multilayered tumor immune resistance. Despite this momentum, clinical implementation remains challenged by antiviral immunity, heterogeneous viral distribution, stromal barriers, and dynamic interferon (IFN) signaling in the TME. Emerging delivery approaches, including carrier cell systems, nanotechnology-enabled viral shielding, and synthetic virology platforms, offer promising solutions to these limitations. Oncolytic virotherapy is rapidly evolving into a multifunctional immunotherapeutic platform capable of reshaping antitumor responses at both local and systemic levels. By integrating advanced viral engineering with rational combination strategies and innovative delivery technologies, OVs hold substantial potential to overcome current barriers in cancer immunotherapy and advance precision oncology. Continued translational research will be essential to fully harness their therapeutic impact and broaden their clinical applicability. Full article

NUT carcinoma (NC) is a rare exceptionally aggressive malignancy, defined by NUTM1 gene translocations, most commonly generating a BRD4::NUTM1 fusion that results in a poor prognosis and limited therapeutic options. Oncolytic virotherapy has emerged as a promising strategy for NC, and the dual bromodomain and extra-terminal domain (BET) and p300/CBP inhibitor NEO2734 has demonstrated potent antiproliferative activity. To investigate multimodal therapeutic approaches that combine epigenetic modulation with immunogenic and cytotoxic effects of oncolytic viruses (OVs), we evaluated two recombinant OVs, including the herpes simplex virus talimogene laherparepvec (T-VEC) and a measles vaccine virus (MeV-GFP), in combination with NEO2734 in four distinct NC cell lines. Viability assays revealed enhanced tumor cell reduction with all combinations, including synergistic effects with T-VEC combinations. Cell cycle analysis showed G1 arrest with NEO2734 alone, whereas its combination with T-VEC resulted in S-phase broadening and reduced G2-phase populations, consistent with replicative stress and increased cytotoxicity. Evaluation of immunogenic cell death (ICD) markers displayed elevated ATP and HMGB1 levels and increased surface calreticulin with T-VEC and NEO2734 combinations. Overall, these findings indicate that combining OVs with BET/p300 inhibitors elicits potent antitumor responses, supports synergistic interactions and immunogenicity, and warrants further investigation in multimodal therapeutic strategies for NC. Full article

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and remains a leading cause of cancer-related mortality worldwide. The management of HCC poses a major therapeutic challenge due to its pronounced molecular heterogeneity, frequent late-stage diagnosis, and intrinsic resistance to both conventional and modern therapeutic modalities. Furthermore, the relatively low tumor mutational burden and the presence of a profoundly immunosuppressive tumor microenvironment (TME) substantially limit the efficacy of immune-based interventions, particularly in advanced disease stages. In recent years, novel immunotherapeutic approaches—including immune checkpoint blockade (ICB), oncolytic virus therapy, and genetically engineered immune cell-based therapies—have garnered significant attention. Nevertheless, durable clinical responses and meaningful improvements in overall survival remain limited, underscoring the complexity of achieving effective immune control in HCC. Emerging evidence suggests that rational combination immunotherapy strategies may offer new therapeutic opportunities by overcoming immune resistance mechanisms. In this review, we provide a comprehensive overview of current therapeutic strategies for HCC, with particular emphasis on immunotherapeutic approaches. We discuss common clinical challenges spanning diagnosis to treatment resistance, critically evaluate key clinical trial outcomes, and highlight future directions aimed at improving therapeutic efficacy and long-term disease control. Full article

Glioblastoma (GBM) is an aggressive tumor with limited therapeutic options. Zika virus (ZIKV) has demonstrated activity against GBM; however, the cellular pathways behind this interaction remain unclear. We systematically reviewed open-access primary studies assessing differentially expressed genes (DEGs) in GBM models infected with wild-type or engineered ZIKV using transcriptomic approaches (inclusion criteria); reviews, restricted-access studies, commentaries, preprints, abstracts, and articles lacking data or not meeting these conditions were excluded (PROSPERO CRD420251077092). We performed a pathway analysis of reported DEGs. PubMed and Google Scholar were searched up to 5 March 2025; 139 records were identified and 5 met the eligibility criteria. Risk of bias was evaluated using an adapted ToxRTool for in vitro experiments and the SYRCLE RoB tool for in vivo models. Altogether, 4360 genes were reported as upregulated and 2072 as downregulated; 12 genes (DNAJB9, SESN2, PMAIP1, PPP1R15A, KLF4, ATF3, IFNB1, IFNL1, ANKRD33B, ZC3HAV1, OASL, and CCL5) were consistently upregulated, none were consistently downregulated. Pathway analysis of the studies providing complete DEG lists identified 23 commonly enriched pathways mostly related to interferon signaling. These findings may help guide future research in this field; nevertheless, methodological heterogeneity limits comparability, reinforcing the need for standardized protocols. Funding: ITpS, CNPq, and FAPEMIG. Full article

Oncolytic coxsackievirus B3 (oCVB3) strain PD-H has shown potent oncolytic efficacy and a remarkable safety profile in the treatment of colorectal cancer in vivo after intratumoral (i.t.) injection. In this study, we investigated the safety and efficiency of PD-H following intravenous (i.v.) virus administration. When injected i.v. into Balb/C mice bearing subcutaneous Colon-26 tumors, PD-H led to slightly reduced tumor progression and a significant increase in animal survival, but it also caused multi-organ infection and tissue damage. To improve the safety profile of PD-H, we inserted microRNA target sites (miR-TS) of the heart-specific miR-1, pancreas-specific miR-375, liver-specific miR-122, and brain-specific miR-124 or the tumor-suppressor miR-145 into the genome of PD-H and generated the viruses PD-622TS and PD-145TS. Both viruses replicated similarly and induced cytotoxicity comparable to that of PD-H in the colorectal carcinoma cell lines Colon-26 and CT-26Luc. Their replication was inhibited in HEK293T cells transiently transfected with the cognate microRNAs. In vivo, i.v. administration of PD-145TS and PD-622TS to healthy Balb/C mouse resulted in significantly lower viral titers in the organs of mice and led to significantly less-intense pathological alterations compared to PD-H. PD-622TS injected i.v. into Balb/C mice with CT-26Luc-induced peritoneal carcinomatosis did not induce off-target alterations in normal organs, but it failed to induce a therapeutic effect. These data indicate that PD-H or microRNA-regulated PD derivatives exhibit only limited therapeutic efficacy following i.v. injection in colorectal tumor-bearing mice. However, the newly engineered microRNA-regulated PD-H variants demonstrate improved safety profiles. Full article

Metastatic uveal melanoma (MUM) remains largely refractory to immune-checkpoint inhibition, so recent research has turned to bispecific T-cell engagers (BTCEs), adoptive-cell therapies (ACTs), and oncolytic viruses (OVs). To summarize the available clinical evidence, we performed a structured literature search across PubMed, Scopus, and Europe PMC for primary studies published between 1 January 2010 and 31 May 2025 that enrolled at least three adults with MUM, treated with one of these modalities, and that reported efficacy or grade-3+ safety outcomes; two reviewers independently performed screening, data extraction, and risk-of-bias assessment, and because of notable heterogeneity, we synthesized the findings narratively. Twenty-two studies met the criteria—thirteen phase I–III trials, eight observational cohorts, and one case series—covering fifteen BTCE cohorts, four ACT cohorts, and three OV cohorts. Tebentafusp, the dominant BTCE evaluated in roughly 1150 HLA-A*02:01-positive patients, extended median overall survival from 16.0 to 21.7 months (hazard ratio 0.51, with three-year follow-up HR 0.68) in its pivotal phase-III trial despite objective response rates of only 5–12%, with early skin rash and week-12 circulating-tumor-DNA clearance emerging as consistent markers of benefit. Tumor-infiltrating lymphocyte therapy, administered to about thirty patients, produced objective responses in 11–35% and occasional durable complete remissions, although median progression-free survival remained 2–6 months and severe cytopenias were universal. Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40–70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events. Full article